title: Donor CD8+ T cells prevent Toxoplasma gondii de-encystation but fail to rescue the exhausted endogenous CD8+ T cell population.
abstract: Functional exhaustion of CD8(+) T cells due to increased expression of inhibitory molecule PD-1 (Programmed Death-1) causes reactivation of latent disease during later phases of chronic toxoplasmosis. Onset of disease recrudescence results in decreased parasite cyst burden concomitant with parasites undergoing stage conversion from a primarily encysted, quiescent bradyzoite to a fast-replicating, highly motile tachyzoite. Thus, reduced cyst burden is one of the early hallmarks of disease recrudescence. This was further validated by depleting gamma interferon (IFN-γ), a cytokine known to control latent toxoplasmosis, in chronically infected prerecrudescent mice. Since CD8(+) T cells (an important source of IFN-γ) lose their functionality during the later phases of chronic toxoplasmosis, we next examined if adoptive transfer of functional CD8(+) T cells from acutely infected donors to the chronically infected prerecrudescent hosts could impede parasite de-encystation and rescue exhausted CD8(+) T cells. While the transfer of immune CD8(+) T cells temporarily restricted the breakdown of cysts, the exhausted endogenous CD8(+) T cell population was not rescued. Over time, the donor population got deleted, resulting in parasite de-encystation and host mortality. Considering that donor CD8(+) T cells fail to become long-lived, one of the cardinal features of memory CD8(+) T cells, it bears the implication that memory CD8 differentiation is impaired during chronic toxoplasmosis. Moreover, our data strongly suggest that while adoptive immunotherapy can prevent parasite de-encystation transiently, reduced antigen burden in the chronic phase by itself is insufficient for rescue of exhausted CD8(+) T cells. The conclusions of this study have profound ramifications in designing immunotherapeutics against chronic toxoplasmosis.
authors.affiliation: Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC, USA.
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Bhadra
authors.forename: Dustin A
authors.initials: DA
authors.lastname: Cobb
authors.forename: Imtiaz A
authors.initials: IA
authors.lastname: Khan
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D016219:Immunotherapy, Adoptive / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D014122:Toxoplasma / Q000276:immunology*; D014123:Toxoplasmosis / Q000276:immunology*
chemical_list: D007371:Interferon-gamma